Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors

被引：126

作者：

Chen, YH ^{[1
]}

Zhang, YH ^{[1
]}

Zhang, HJ ^{[1
]}

Liu, DZ ^{[1
]}

Gu, M ^{[1
]}

Li, JY ^{[1
]}

Wu, F ^{[1
]}

Zhu, XZ ^{[1
]}

Li, J ^{[1
]}

Nan, F ^{[1
]}

机构：

[1] Chinese Acad Sci, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai Inst Mat Med,Inst Biol Sci,Grad Sch, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 05期

关键词：

D O I：

10.1021/jm050896o

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of isoquinoline-1,3,4-trione derivatives were identified as novel and potent inhibitors of caspase-3 through structural modification of the original compound from high-throughput screening. Various analogues (2, 6, 9, 13, and 14) were synthesized and identified as caspase inhibitors, and the introduction of a 6-N-acyl group (compound 13) greatly improved their activity. Some of them showed low nanomolar potency against caspase-3 in vitro (for example, for 6k, IC50 = 40 nM) and significant protection against apoptosis in a model cell system. Additionally, compound Of demonstrated a dose-dependent decrease in infarct volume in the transient MCA occlusion stroke model. The present small-molecule caspase-3 inhibitor with novel structures different from structures of known caspase inhibitors revealed a new direction for therapeutic strategies directed against diseases involving abnormally up-regulated apoptosis.

引用

页码：1613 / 1623

页数：11

共 35 条

[1] Identification of potent and novel small-molecule inhibitors of caspase-3 [J].